Process for preparing ergoline derivatives

ABSTRACT

Ergoline derivatives of the formula I: ##STR1## wherein R represents hydrogen or C 1  -C 4  alkyl; R 1  represents hydrogen, chlorine, bromine or methyl; either R 2  and R 3  both represent hydrogen or together represent a chemical bond; R 4  represents a C 1  -C 4  hydrocarbon group; each of R 5 , R 6 , R 8  and R 9  independently represents hydrogen or C 1  -C 4  alkyl; R 7  represents hydrogen, C 1  -C 4  alkyl, phenyl or C 3  -C 7  cycloalkyl and n is 0, 1 or 2; are prepared by reaction between compounds of the formulae II and III: ##STR2## and subsequent cyclization of the resultant compounds. The compounds of the formula I are known useful anxiolytic, antipsychotic and anti-parkinson agents.

The present invention provides a process for the preparation of knownergoline derivatives having the formula I: ##STR3## wherein R representsa hydrogen atom or a C₁ -C₃ alkyl group; R₁ represents a hydrogen,chlorine or bromine atom or a methyl group; either R₂ and R₃ representhydrogen atoms or R₂ and R₃ together represent a chemical bond; R₄represents a hydrocarbon group having from 1 to 4 carbon atoms; each ofR₅, R₆, R₈ and R₉ independently represents a hydrogen atom or an alkylgroup having from 1 to 4 carbon atoms; R₇ represents a hydrogen atom, analkyl group having from 1 to 4 carbon atoms, a phenyl group or acycloalkyl group having from 3 to 7 carbon atoms and n is 0, 1 or 2.

In the definition of R₄, a hydrocarbon group having from 1 to 4 carbonatoms is intended to include alkyl, cycloalkyl and unsaturated (bothethylenically and acetylenically) groups.

Representative moieties include methyl, ethyl, n-propyl, isopropyl,butyl, t-butyl, isobutyl, methylcyclopropyl, allyl and propargyl.

The invention provides a process comprising (i) reacting an ergoline ofthe formula II with α-halogen derivatives of formula III to affordergoline derivatives of formula IV ##STR4## wherein n, R, R₁, R₂, R₃,R₅, R₆, R₈ and R₉ have the above given meanings, R₁₀ and R₁₁ areindependently C₁ -C₄ alkoxy group such as ethoxy or methoxy group or anamino group NH-R₇ wherein R₇ is as above defined, X is halogen atom suchas chlorine or bromine; and R'₄ represents a hydrocarbon group havingfrom 1 to 4 carbon atoms or a N-protecting group such as acetyl,tert-butyloxycarbonyl or trichloroethyloxycarbonyl group;

(ii) if R'₄ is a N-protecting group in the resultant compound of theformula IV, converting the said compound by deprotection and alkylationinto a corresponding compound of the formula IV in which R'₄ is C₁ -C₄hydrocarbon group;

(iii) if R₁₀ and R₁₁ both represent alkoxy groups in the resultantcompound of formula IV, converting the said compound by ammonolysis intoa corresponding compound of formula IV in which R₁₀ and R₁₁ are bothamino groups; and

(iv) cyclising a said compound of formula IV in which at least one ofR₁₀ and R₁₁ represents an amino group NHR₇ wherein R₇ is as definedabove.

The wavy line in formulae I, II and IV indicates that the substituent inthe 8-position may be in the α-configuration, i.e. below the plane ofthe ring, in the β-configuration, i.e. above the plane of the ring, orin both, i.e. a mixture of derivatives of formula I, II or IV is presentwith some having the substituent in the 8-position in theα-configuration and the rest having the substituent in the 8-position inthe β-configuration (a diastereoisomeric mixture).

The condensation process (i) is carried out in an organic solvent suchas toluene, acetonitrile, or dimethylformamide in presence of an acidscavenger such as an inorganic carbonate or triethylamine. When thereaction is complete the solvent is removed and the residue is purifiedby crystallization or chromatography according to well known techniques.

If necessary, a compound of formula IV in which R'₄ is a N-protectinggroup may be converted into another compound of the formula IV in whichR'₄ is a C₁ -C₄ hydrocarbon group by deprotection with a base, formicacid or Zn/dust followed by alkylation with an appropriate halidederivative (R₄ -Hal) in the presence of an acid scavenger.

The compounds of formula IV in which R'₄ is a N-protecting group arepreferred starting compounds when n is 1 and the substituent in the8-position is in the α-configuration.

If necessary, a compound of formula IV in which R₁₀ and R₁₁ are bothalkoxy groups may be converted into another compound of the formula IVin which R₁₀ and R₁₁ are both amino groups by ammonolysis in a suitablesolvent such as methanol, ethanol or dimethylformamide.

According to the present invention, the intermediate derivatives offormula IV are then cyclized to give the derivatives of formula I. Inparticular, when R₁₀ and R₁₁ are both amino groups the cyclization togive an ergoline derivative of the formula I where R₇ is a hydrogen atomcan be accomplished by heating in suitable solvents such as phenol,xylenol or cresol in the range of temperature varying from 100° to 200°C.

When R₁₀ is an alkyloxy group and R₁₁ is an amino group NH-R₇ thecyclization to give an ergoline derivative of the formula I can becarried out by heating in vacuo at the melting point of the compound offormula IV or by the hydrolysis of the COR₁₀ group and subsequenttreatment with a suitable condensing agent such as acetic anhydride,alkylchlorocarbonate or diimidazolcarbonyl in a solvent such astetrahydrofuran, 1,4-dioxane or dimethylformamide within the range oftemperature of from 50°-150° C.

The starting compounds of formulae II and III which are employed in theprocess according to the invention are known compounds or may beprepared by established procedures starting from known compounds. Forexample, the compounds of the formula II and their preparation aredescribed in our EP-A-0126968.

The compounds of formula I and their pharmaceutically acceptable saltsare useful anxiolytic, antipsychotic and anti Parkinson agents, asdescribed in EP-A-197,241, U.S. Pat. No. 4,847,253 and WO 90/04396. Theergoline derivatives of formula I prepared by the present process maytherefore be formulated as a pharmaceutical composition. The compositionalso comprises a pharmaceutically acceptable carrier or diluent.

The preparation of compounds of general formula I is described in theabove cited EP-A-0197,241. Although the process there described iscapable of producing derivatives of the general formula I, the processhere described is more versatile allowing the synthesis of a highernumber of derivatives of general formula I especially when R₂ and R₃together represent a chemical bond.

The following Examples illustrate the invention.

EXAMPLE 1 1-Phenyl-4-(6-methyl-9,10-ergolen-8β-yl)-methylpiperazin-2,6-dione

A solution of 5.08 g (0.015 m) ofN-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycine ethyl ester and 1.03 g(0.0075 m) of potassium carbonate and 3.85 g (0.018 m) ofN-phenylbromoacetamide in 200 ml of dimethylformamide was stirred at 50°C. for 4 hours.

The resulting solution was poured into brine and the precipitate wasextracted with ethyl acetate. Removal of the solvent and crystallizationfrom ethanol afforded 6.5 g ofN-phenylcarbamoylmethyl-N-[(6-methyl-9,10-ergolen-8β-yl)-methyl]-glycineethyl ester m.p. 196°-197° C.

A solution of 6.5 g (0.013 m) of this ester in 50 ml of ethanol wastested with 17.9 ml of sodium hydroxide 1M and the resulting solutionwas heated at 80° C. for 30 minutes. After acidification with 179 ml ofhydrochloric acid 1M, the resulting solution was poured into ice water.The precipitate was filtered off and then washed with water, acetone anddried giving 5.1 g ofN-phenylcarbamoylmethyl-N-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycine.m.p. 252°-255° C. To a suspension of 5 (0.011 m) ofN-phenylcarbamoylmethyl-N-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycinein 50 ml of anhydrous dioxane was added portionwise 1.96 g (0.121 m) ofN,N'-diimidazole carbonyl. The resulting solution was refluxed for 3hours. After removal of the solvent, the residue was poured intochloroform and extracted with a 10% ammonium hydroxide solution. Theorganic phase was washed with brine and after drying evaporated todryness. After crystallization from acetone, 4.1 g of the titlecompounds were obtained m.p. 240°-245° C.

EXAMPLE 2 4-(6-Methyl-9,10-ergolen-8β-yl)methylpiperazin-2,6-dione

Operating as in Example 1, but employing bromoacetamide in place ofN-phenylbromoacetamide,N-carbamoylmethyl-N-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycine ethylester was obtained m.p. 172°-74° C. From thisN-carbamoylmethyl-N-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycine wasobtained m.p. 242°-243° C. Finally the title compound was obtained in75% yield m.p. 224°-225° C.

EXAMPLE 3 4-(1,6-Dimethyl-9,10-ergolen-8β-yl)methylpiperazin-2,6-dione

Operating as in Example 2, but employingN-[(1,6-dimethyl-9,10-ergolen-8β-yl)methyl]-glycine ethyl ester in theplace of N-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycine ethyl ester,N-carbamoylmethyl-N-[(1,6-dimethyl-9,10-ergolen-8β-yl)methyl]-glycineethyl ester was obtained m.p. 180°-183° C. From thisN-carbamoylmethyl-N-[(1,6-dimethyl-9,10-ergolen-8β-yl)methyl]-glycinewas obtained. m.p. and finally the title compound was obtained in 55%yield m.p. 216°-218° C.

EXAMPLE 44-(2-Bromo-6-methyl-9,10-ergolen-8β-yl)methylpiperazin-2,6-dione

Operating as in Example 1, but employing ethyl bromoacetate in place ofN-phenylbromoacetamide, andN-[(2-bromo-6-methyl-9,10-ergolen-8β-yl)methyl]-glycine ethyl ester inplace of N-[(6-methyl-9,10-ergolen-8β-yl)methyl]-glycine ethyl ester,N-ethoxycarbonylmethyl-N-[(2-bromo-6-methyl-9,10-ergolen-8β-yl)methyl]-glycineethyl ester was obtained m.p. 93°-96° C.

A solution of 10 g of this ester in 100 ml of methanol saturated withgaseous ammonia was aged at room temperature for 24 hours. Concentrationmixture afforded N-carbamoylmethyl-N-[(2-bromo-6-methyl-9,10-ergolen-8β-yl)methyl]-glycine amide in85% yield m.p. 218°-221° C.

A mixture of 5 g ofN-carbamoylmethyl-N-[(2-bromo-6-methyl-9,10-ergolen-8β-yl)methyl]glycinamideand 30 g of phenol was heated under nitrogen at 160° C. for 30 minutes.After cooling, the reaction mixture was taken up in diethyl ether andthe precipitate was crystallized twice from acetone affording 3.9 g ofthe title compound m p. 242°-245° C.

What is claimed is:
 1. A process for preparing an ergoline derivative ofthe formula I: ##STR5## wherein R represents a hydrogen atom or a C₁ -C₃alkyl group; R₁ represents a hydrogen atom, chlorine, bromine atom or amethyl group; either R₂ and R₃ represent hydrogen atoms or R₂ and R₃together represent a chemical bond; R₄ represents a hydrocarbon grouphaving from 1 to 4 carbon atoms selected from the group consisting ofalkyl, cycloalkyl, ethylenically unsaturated and acetylenicallyunsaturated groups; each of R₅, R₆, R₈ and R₉ independently represents ahydrogen atom or an alkyl group having from 1 to 4 carbon atoms, aphenyl group or a cycloalkyl group having from 3 to 7 carbon atoms and nis 0, 1 or 2, which process comprises reacting an ergoline of theformula II with an α-halogen derivative of the formula III: ##STR6##wherein n, R, R₁, R₂, R₃, R₅, R₆, R₈ and R₉ have the above givenmeanings, R₁₀ and R₁₁ independently represent a C₁ -C₄ alkoxy group oran amino group NHR₇ wherein R₇ is as defined above, X represents ahalogen atom, R'₄ represents a hydrocarbon group having from 1 to 4carbon atoms selected having from 1 to 4 carbon atoms selected from thegroup consisting of alkyl, cycloalkyl, ethylenically unsaturated andacetylenically unsaturated groups or a N-protecting group and, ifnecessary, converting the resultant compound of the formula IV: ##STR7##wherein R, R₁, R₂, R₃, R₅, R₆, R₈, R₉ and n are as defined above, R₁₀and R₁₁ independently represent a C₁ -C₄ alkoxy group or an amino groupNHR₇ wherein R₇ is as defined above and R'₄ is a N-protecting group intoa compound of the formula IV in which R'₄ is a C₁ -C₄ hydrocarbon groupselected from the group consisting of alkyl, cycloalkyl, ethylenicallyunsaturated and acetylenically unsaturated groups by deprotection andalkylation, if necessary converting the compound of the formula IV inwhich R₁₀ and R₁₁ both represent an alkoxy group into a compound of theformula IV in which R₁₀ and R₁₁ are both amino groups by ammonolysis;and cyclizing a said compound of the formula IV in which at least one ofR₁₀ and R₁₁ represents an amino group NHR₇ is as defined above.
 2. Aprocess according to claim 1 in which the reaction between the compoundsof the formulae II and III is carried out in an organic solvent selectedfrom the group consisting of toluene, acetonitrile and dimethylformamideand in the presence of an acid scavenger which is an inorganic carbonateor triethylamine.
 3. A process according to claim 1 in which thecyclization of the compound of the formula IV wherein R₁₀ and R₁₁ bothrepresent amino groups is carried out by heating in a solvent at atemperature of from 100° to 200° C.
 4. A process according to claim 3 inwhich the solvent is phenol, xylenol or cresol.
 5. A process accordingto claim 1 in which the cyclization of the compound of the formula IVwherein R₁₀ is an alkoxy group and R₁₁ represents a said group NHR₇ iscarried out by heating in vacuo at the melting point of the compound offormula IV or by hydrolysis of the COR₁₀ carboxylate group andsubsequent treatment with a condensing agent in a solvent at atemperature of from 50° to 150° C.
 6. A process according to claim 5 inwhich the condensing agent is acetic anhydride, alkylchlorocarbonate ordiimidazolcarbonyl and the solvent is tetrahydrofuran, 1,4-dioxane ordimethylformamide.